General Information

Nuvigil (armodafinil) is a single-isomer of modafini. The exact mechanism of action is unknown. Armodafinil belongs to a class of drugs known as eugeroics, which are stimulants that provide long-lasting mental arousal.

Nuvigil is specifically indicated to improve wakefulness in patients with excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome (OSAHS), narcolepsy and shift work sleep disorder (SWSD).

Nivigil is supplied as a 50 mg, 150 mg or 250 mg tablet designed for oral administration. The recommended initial dose of the drug for the treatment of OSAHS and narcolepsy is 150 mg or 250 mg given as a single dose in the morning. The recommended initial dose of the drug for the treatment of SWSD is 150 mg given daily approximately one hour prior to the start of the work shift.

Clinical Results

FDA Approval
FDA approval of Nuvigil was based on the results of four clinical trials. In each trial a p-value of less than 0.05 was required for statistical significance.
Obstructive Sleep Apnea/Hypopnea Syndrome (OSAHS)
Two 12-week, multi-center, placebo-controlled, parallel-group, double-blind trials were conducted. The primary endpoints for both trials included sleep latency, as assessed by the Maintenance of Wakefulness Test (MWT) and the change in overall disease status, as measured by the Clinical Global Impression of Change (CGI-C) at the final visit.
Study One
This trial enrolled 395 OSAHS subjects who were randomized to receive Nuvigil 150 mg/day, Nuvigil 250 mg/day or matching placebo. Subjects treated with Nuvigil showed a statistically significant improvement in the ability to remain awake compared to placebo-treated subjects as measured by the MWT at final visit. Statistical significance was also seen in overall disease status based on the CGI-C scale. The average sleep latencies in minutes on the MWT for the 150 mg group were 21.5 at baseline with a 1.7 change from baseline, the 250 mg group 23.3 at baseline with a 2.2 change and placebo 23.2 at baseline with a -1.7 change. The CGI-C changes for the 150 mg group showed 71% of subjects improved, for the 250 mg group 74% improved versus 37% improved in the placebo group.
Study Two
This trial enrolled 263 OSAHS subjects who received Nuvigil 150 mg/day or placebo. Subjects receiving Nuvigil showed a statistically significant improvement compared to placebo in their ability to remain awake as measured by MWT. The baseline for the Nuvigil group was 23.7 with a 2.3 change from baseline versus a 23.3 measurement at baseline for the placebo group with a -1.3 change from baseline. Statistical significance was also observed in the CGI-C measurements, with a 71% improvement in the Nuvigil arm compared to a 53% improvement in the placebo arm.
Narcolepsy
This 12-week, multi-center, placebo-controlled, parallel-group, double-blind study enrolled 196 subjects clinically diagnosed with narcolepsy. Subjects were randomized to receive Nuvigil 150 or 250 mg/day or placebo. The primary endpoints were latency to sleep onset, measured by the Maintenance of Wakefulness Test (MWT) and the change in overall disease status measured by the Clinical Global Impression of Change (CGI-C). The subjects treated with Nuvigil showed a statistically significantly enhanced ability to remain awake on the MWT at each dose compared to placebo at the final visit. At baseline the 150 mg Nuvigil group score was 12.1 and had a 1.3 change from baseline; the 250 mg Nuvigil had a baseline score of 9.5 with a 2.6 change from baseline and the placebo group had a baseline score of 12.5 with a -1.9 change from baseline. Overall clinical condition was also significantly improved over baseline as measured by the CGI-C. In the Nuvigil 150 mg group, 69% of the subjects improved and in the 250 mg group 73% of the subjects improved versus 33% for placebo.
Shift Work Sleep Disorder (SWSD)
This 12-week, multi-center, double-blind, placebo-controlled, parallel group trial enrolled 254 subjects who were symptomatic for SWSD for at least three months. The subjects were also required to work the night shift at least 5 times per week. Subjects were randomized to receive 150 mg/day Nuvigil or placebo. The primary endpoints were sleep latency as measured by the Multiple Sleep Latency Test (MSLT) performed during a simulated night shift at the final visit and change in overall disease status measured by the CGI-C. The subjects receiving Nuvigil showed a statistically significant improvement over placebo in prolongation in time to sleep onset. In the Nuvigil group the baseline measurement was 2.3 with a 3.1 change from baseline versus a baseline score of 2.4 for placebo and a change from baseline of 0.4. Significant improvement in overall disease status was seen in the CGI-C scores, with 79% of the Nuvigil arm reporting a change versus 59% of the placebo arm.
Ongoing Study Commitments

• Cephalon has agreed to a deferred pediatric study under PREA to improve wakefulness in patients with excessive sleepiness associated with narcolepsy in pediatric patients ages 6 to 17.
  Final Report Submission: June 2015
• Cephalon has agreed to conduct a 2-year oral (gavage) carcinogenicity study of armodafinil in mouse.
  Protocol Submission: April 2008
  Study Start: August 2008
  Final Report Submission: August 2011
• Cephalon has agreed to provide a Pregnancy Registry protocol for Nuvigil to obtain systematically collected data on the effects of exposures during pregnancy, labor, and delivery in women of child-bearing age.
  Protocol Submission: July 2007
  Implementation: Upon concurrence with the Agency
• Cephalon has agreed to provide a thorough literature search to determine whether there is any information on the P-glycoprotein induction potential of modafinil in vivo.
  Final Report Submission: June 2008
• Cephalon has agreed to conduct a comprehensive literature search for any in-vivo Pglycoprotein drug-drug interaction information.
  Final Report Submission: June 2008

Side Effects

Adverse events associated with the use of Nuvigil may include, but are not limited to, the following:

• Headache
• Nausea
• Dizziness
• Insomnia
• Dry mouth
• Anxiety
• Diarrhea
• Rash

Mechanism of Action

Nuvigil (armodafinil) is a single-isomer of modafini. The exact mechanism of action is unknown. Armodafinil belongs to a class of drugs known as eugeroics, which are stimulants that provide long-lasting mental arousal. Pharmacologically, armodafinil does not bind to or inhibit several receptors and enzymes potentially relevant for sleep/wake regulation. Armodafinil is not a direct- or indirect-acting dopamine receptor agonist. However, in vitro, both armodafinil and modafinil bind to the dopamine transporter and inhibit dopamine reuptake.

Literature References

Erman MK, Rosenberg R, For The U S Modafinil Shift Work Sleep Disorder Study Group Modafinil for excessive sleepiness associated with chronic shift work sleep disorder: effects on patient functioning and health-related quality of life. Primary care companion to the Journal of clinical psychiatry 2007;9(3):188-94

Hirshkowitz M, Black J Effect of adjunctive modafinil on wakefulness and quality of life in patients with excessive sleepiness-associated obstructive sleep apnoea/hypopnoea syndrome: a 12-month, open-label extension study. CNS Drugs 2007;21(5):407-16

Hirshkowitz M, Black JE, Wesnes K, Niebler G, Arora S, Roth T Adjunct armodafinil improves wakefulness and memory in obstructive sleep apnea/hypopnea syndrome. Respiratory Medicine 2007 Mar;101(3):616-27

Harsh JR, Hayduk R, Rosenberg R, Wesnes KA, Walsh JK, Arora S, Niebler GE, Roth T The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness associated with narcolepsy. Current Medical Research and Opinion 2006 Apr;22(4):761-74

Wong YN, Simcoe D, Hartman LN, Laughton WB, King SP, McCormick GC, Grebow PE. A double-blind, placebo-controlled, ascending-dose evaluation of the pharmacokinetics and tolerability of modafinil tablets in healthy male volunteers. Journal of Clinical Pharmacology 1999 Jan;39(1):30-40

Additional Information

For additional information regarding Nuvigil or excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome (OSAHS), narcolepsy and shift work sleep disorder (SWSD), please visit the Nuvigil web page.